The fundamental hypothesis guiding this proposal is that treatments, known to initiate spinal serotonin- dependent plasticity in respiratory motor output, strengthen synaptic pathways to phrenic motoneurons, thereby improving respiratory function during recovery from spinal cord injury. In the previous three years of this project period, we demonstrated that both acute and chronic intermittent hypoxia initiate serotonin- dependent respiratory plasticity, converting existing but functionally ineffective pathways to effective pathways. Further, these effects were greatest in rats with chronic spinal injuries, demonstrating that unique features of the injured spinal cord influence the expression of spinal plasticity. The discovery of a potential treatment that is most effective in animals with chronic injuries is unique, since few therapeutic options are available beyond the acute phase of injury, and the capacity for spontaneous functional improvements is limited or has ended during chronic injury. In the next five year period of this grant, Wepropose to focus on an intermediate form of intermittent hypoxia, namely daily acute intermittent hypoxia (dAIH). We hypothesize that dAIH will combine the enduring effects of more severe protocols of intermittent hypoxia, but without adverse side-effects such as systemic hypertension or hippocampal cell death. We propose to: 1) investigate the effects of dAIH on crossed spinal synaptic pathways to phrenic motoneurons below a cervical spinal injury (hemisection or contusion); 2) test the hypothesis that dAIH has enduring functional consequences in restoring ventilatory capacity; 3) test the hypothesis that increased BDNF within phrenic motoneurons is necessary and sufficient for dAIH-induced plasticity in crossed spinal pathways; and 4) test the hypothesis that small molecules that trans-activate the relevant BDNF receptor (TrkB) elicit similar plasticity, but downstream from the potentially harmful effects of hypoxia. These aims will be performed using a multidisciplinary approach with rats as an experimental model. State-of-the-art techniques include the use of small interfering RNAs to dissect cellular/molecular mechanisms of dAIH-induced plasticity in vivo. Collectively, these experiments suggest an unprecedented approach to restore respiratory motor function following chronic spinal injuries. Further, the conceptual advances promised from these studies may be applicable to other disorders of respiratory control, including neurodegenerative diseases such as ALS.